Field of the Invention
This invention relates to a pharmaceutical composition comprising a testosterone derivative (such as testosterone undecanoate) having a log P of at least 5 and a vehicle, and this is intended for oral use. Typically, the oral dosage form is a solid dosage form that has a high oral bioavailability of testosterone and at the same time a low variability in absorption compared to prior oral formulations of testosterone and is being delivered via the lymphatic transport system. The oral dosage, such as solid dosage form, further has the advantage of having a reduced or an absence of food effect and it can therefore be taken in both fed and fasted state. This invention also relates to the preparation and composition of a stable solid oral dosage form and methods of use thereof, for instance in treatment of conditions associated with a deficiency or absence of endogenous testosterone in a mammal in need thereof. Typically the composition is administered orally as a testosterone replacement therapy.
Background of the Invention
Testosterone and derivatives thereof, such as Testosterone Undecanoate and Methyltestosterone are indicated as replacement therapy in conditions associated with a deficiency or absence of endogenous testosterone. These products come in a variety of formulations including: gels, patches, injections and oral capsules.
Testosterone is a poorly water-soluble compound. When administered orally Testosterone undergoes extensive first pass metabolism both during absorption in the GI tract and in the liver. Testosterone given orally is known to be mostly deactivated by the liver and intestinal cell lining before reaching circulation. Derivatives of testosterone such as Testosterone Undecanoate and Methyltestosterone have therefore been developed and marketed for oral delivery. Methyltestosterone is a prodrug of testosterone and has a close structural similarity with testosterone but has a methyl group at C17 (17-α derivative) in order to increase oral bioavailability. Methyltestosterone is marketed as Android®, Testered® and Virilon® but is associated with liver toxicity limiting its use. Testosterone Undecanoate (TU) is a lipophillic ester product of Testosterone. Testosterone undecanoate, is non hepatoxic in contrast to 17-α derivative and is marketed as Andriol® or Andriol® Testocaps™ in many countries for oral administration. Testosterone undecanoate is formulated in Castor oil/Propylene glycol monolaurate (293 mg mixture) in a soft gelatin capsule. According to its label, the testosterone undecanoate is co-absorbed with a lipophilic solvent from the intestine into the lymphatic system, thus circumventing the first-pass inactivation by the liver. During absorption testosterone undecanoate is partly reduced to dihydrotestosterone undecanoate. From the lymphatic system it is released into the plasma. In plasma and tissues both testosterone undecanoate and dihydrotestosterone undecanoate are hydrolyzed to yield the natural male androgens testosterone and dihydrotestosterone. The formulation should however always be taken with a normal meal to ensure absorption as the absorption of testosterone undecanoate. Thus the absorption is extremely dependent on food intake which makes absorption variable and often inadequate. According to the Andriol® label, the oral bioavailability of testosterone undecanoate in a patient in a fed state is more than 50 times that of a patient in a fasted state. The capsules must therefore be taken with the morning and evening meal. Due to this food effect, oral testosterone undecanoate is not a suitable therapy for patients who have a low food or low fat intake, such as many elderly patients. Additionally, one of the main draw backs of this oral formulation is the variability in absorption and thereby unreliable oral bioavailability and fluctuation in serum levels which results in unreliable efficacy.
To be successful in drug formulations targeted for lymphatic absorption the API has to have a high Log P value and a high solubility in lipids. In the case of TU both these criteria are met and therefore TU is a good candidate for lymphatic absorption.
Schnabel et al. (Clin. Endocrin., vol. 66, 579-585, 2007) found that for effective lymphatic absorption of Andriol® Testocaps in humans, 19 g of food lipid was found to be needed, whereas 5 g of lipid led to poor absorption. Two Andriol® Testocaps corresponding to totally 80 mg TU were dosed in the study. The dosed capsules contained total 586 mg of castor oil:propylene glycol monolaurate (60:40 w/w) corresponding to only 350 mg long chain fat. From the study it was also concluded that inter subject variation was inversely correlated to lipid intake. At high lipid intake the bioavailability was found to be fairly reproducible whereas the variation was very high at low fat intake (up to 40% for AUC).
Lymphatic absorption is a complex process which will be influenced by the formulation as well as the food taken at the time of dosing. In literature it is described that lipophillic drugs with high Log P values can be absorbed into the enterocytes and be incorporated into lipoproteins inside the enterocytes. The drug has to dissolve in the GI-tract and pass the unstirred water layer prior to absorption into the enterocytes. To achieve this, drugs can “hide” in micelles formed either from lipid digestion products and bile or from surfactants present in the formulation.
Fatty acids and monoglycerides are taken up at the same time and re-synthesized to triglycerides, which forms the center of the lipoproteins. Those lipoproteins are then exocytosed from the enterocytes into the lumen and have to diffuse to the lymph. This transport of drug can be increased by increasing the flow of lipoproteins, which again will depend on the amount of lipids in the gut.
As fatty acids and monoglycerides are critical to this absorption mechanism, they have to be supplied either from food or from the formulation of the drug. This can be in the form of fats, monoglycerides or fatty acids. Fats need to be digested to fatty acids and monoglycerides by enzymes in stomach and intestine to be absorbed. Better dispersion to small droplets will help digestion by increasing surface of fat particles giving access for enzymes. In literature different combinations of fats, glycerides or fatty acids have been tested for influence on lymphatic absorption. No general agreement has been reached to which combinations are optimal but from literature it is clear that the fat composition play an important role as well as the amount of fat taken. Khoo et al (Pharm. Res., vol. 20, 1460-1464, 2003) demonstrated that a formulated fat composition of only 600 mg was enough to trigger lipid metabolism in the GI tract and induce high lymphatic absorption of the compound Halofantrine in fasted dogs. Further, the exogenous lipid supplied in the formulation was demonstrated to induce transport of endogenous lipid, as a 5-fold flow of lipid was found to be transported to the lymph, compared to the lipid from the formulation.